RESUMEN
The neuronal system that controls respiration creates plasticity in response to physiological changes. Chronic sustained hypoxia causes neuroplasticity that contributes to ventilatory acclimatization to hypoxia (VAH). The purpose of this study is to explain the potential roles of the VAH mechanism developing because of chronic sustained hypoxia on respiratory neuroplasticity of vascular endothelial growth factor (VEGF) receptor activation on the nucleus tractus solitarius (NTS) and phrenic nerve. In this study 24 adult male Sprague-Dawley rats were used. Subjects were separated into four groups, a moderate-sham (mSHAM), severed-sham (sSHAM), moderate chronic sustained hypoxia (mCSH), and severed chronic sustained hypoxia (sCSH). Normoxic group (mSHAM and sSHAM) rats were exposed to 21% O2 level (7 days) in the normobaric room while hypoxia group (mCSH and sCSH) rats were exposed to 13% and 10% O2 level (7 days). Different protocols were applied for normoxic and hypoxia groups and ventilation, respiratory frequency, and tidal volume measurements were made with whole-body plethysmography. After the test HIF-1α, erythropoietin (EPO), and VEGFR-2 expressions on the NTS region in the medulla oblongata and phrenic nerve motor neurons in spinal cord tissue were analyzed using the immunohistochemical stain method. Examinations on the medulla oblongata and spinal cord tissues revealed that HIF-1α, EPO, and VEGFR-2 expressions increased in hypoxia groups compared to normoxic groups while a similar increase was also seen when respiratory parameters were assessed. Consequently, learning about VAH-related neuroplasticity mechanisms developed as a result of chronic continuous hypoxia will contribute to developing new therapeutical approaches to various diseases causing respiratory failure using brain plasticity without recourse to medicines.
Asunto(s)
Hipoxia/fisiopatología , Plasticidad Neuronal/fisiología , Nervio Frénico/fisiopatología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Núcleo Solitario/fisiopatología , Animales , Enfermedad Crónica , Masculino , Ratas , Ratas Sprague-Dawley , RespiraciónRESUMEN
Pancreatic neuroendocrine neoplasms (panNENs) are the second most common epithelial tumors of the pancreas. Despite improvements in prognostic grading and staging systems, it remains a challenge to predict the clinical behavior of panNENs and the response to specific therapies given the high degree of heterogeneity of these tumors. Most panNENs are nonfunctional and present as advanced disease. However, systemic therapies provide modest benefits. Therefore, there is a need for predictive biomarkers to develop personalized treatment and to advance new drug development. The somatostatin receptors remain the only clinically established prognostic and predictive biomarkers in panNENs. Oncogenic drivers are at a very low frequency. Commonly mutated genes in panNENs include MEN1, chromatin remodeling genes (DAXX and ATRX), and mammalian target of rapamycin pathway genes. In contrast, poorly differentiated neuroendocrine carcinomas (panNECs), which carry a very poor prognosis, have distinctive mutations in certain genes (eg, RB1 and p53). Ongoing research to integrate epigenomics will provide tremendous opportunities to improve current understanding of the clinical heterogeneity of pancreatic neuroendocrine tumors and provide invaluable insight into the biology of these tumors, new drug development, and establishing personalized therapies.
Asunto(s)
Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/genética , Inestabilidad Cromosómica , Reparación del ADN , Epigénesis Genética , Humanos , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Receptores de Somatostatina/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
Blood vessels supply oxygen and nutrients to all the cells in a living body, and provide essential transport routes for collecting waste products. For these functions, blood vessel networks should be appropriately formed in each tissue. Therefore, blood vessels are one of the earliest organs formed during the developmental process. Development of the blood vessel system promotes tissue differentiation and organ morphogenesis, allowing each organ to maintain its unique functions under changing metabolic conditions. Blood vessels have a relatively simple structure, consisting of endothelial cells covering the inner layer, and pericytes or smooth muscle cells surrounding the outside. The structure of the vascular network is extremely diverse, with blood vessels uniquely organized depending on the tissues they serve, to create tissue-specific microenvironments. How are such tissue-specific vascular environments generated? Over the years, anatomical findings have accumulated to confirm this vascular diversity. However, the molecular basis for this diversity has remained unclear. In the present article, we review the mechanisms of coordinated developmental control of the vascular and neural systems in the cerebral cortex from the viewpoint of the accurate expression control of vascular endothelial growth factor (VEGF) signaling, and describe future perspectives.
Asunto(s)
Corteza Cerebral/irrigación sanguínea , Neovascularización Fisiológica/genética , Transducción de Señal/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Expresión Génica , Humanos , Sistema Linfático/fisiología , Ratones , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
The impacts of chronic bisphenol A (BPA) exposure suspected to be a potential risk factor for breast cancer progression are not thoroughly understood in different subtypes of breast cancer cells (BCCs). This study aimed to compare the differentially expressed genes (DEGs) and biological functions in MCF-7 (luminal A), SK-BR3 (HER2-enriched) and MDA-MB-231 (triple-negative) cells exposed to BPA at an environmentally human-relevant low dose (10-8â¯M) for 30â¯days, by using the approach of RNA sequencing and online informatics tools. BPA-exposure resulted in 172, 137, and 139 DEGs in MCF-7/BPA, SK-BR3/BPA, and MDA-MB-231/BPA, respectively. The significantly enriched gene ontology terms of DEGs in each cell were different: cellular response to gonadotropin-releasing hormone, negative regulation of fibrinolysis, choline metabolism, glutamate signaling pathways and coagulation pathway in MCF-7/BPA; positive regulation of inflammatory response and VEGF/VEGFR signaling pathways in SK-BR3/BPA; negative regulation of keratinocyte proliferation and HIF signaling pathways in MDA-MB-231/BPA cells. The immune network analysis of DEGs across the breast cancer cells indicated NKT, NK and T cell activation and dendritic cell migration by regulating the expression of immunomodulatory genes. High expression of IL19, CA9 and SPARC identified in MCF-7/BPA, SK-BR3/BPA, and MDA-MB-231/BPA are detrimental gene signatures to predict poor overall survival in luminal A, HER2-enriched and triple-negative breast cancer patients, respectively. These findings indicate chronic BPA exposure has dissimilar impacts on the regulation of gene expression and diverse biological functions, including immune modulation, in different subtypes of BCCs.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Fenoles/toxicidad , Transcriptoma/efectos de los fármacos , Antígenos de Neoplasias/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Anhidrasa Carbónica IX/genética , Línea Celular Tumoral , Humanos , Interleucinas/genética , Osteonectina/genética , Receptores de Factores de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
OBJECTIVE: We examined the pathogenic significance of VEGF (vascular endothelial growth factor)-A in experimental abdominal aortic aneurysms (AAAs) and the translational value of pharmacological VEGF-A or its receptor inhibition in aneurysm suppression. Approaches and Results: AAAs were created in male C57BL/6J mice via intra-aortic elastase infusion. Soluble VEGFR (VEGF receptor)-2 extracellular ligand-binding domain (delivered in Ad [adenovirus]-VEGFR-2), anti-VEGF-A mAb (monoclonal antibody), and sunitinib were used to sequester VEGF-A, neutralize VEGF-A, and inhibit receptor tyrosine kinase activity, respectively. Influences on AAAs were assessed using ultrasonography and histopathology. In vitro transwell migration and quantitative reverse transcription polymerase chain reaction assays were used to assess myeloid cell chemotaxis and mRNA expression, respectively. Abundant VEGF-A mRNA and VEGF-A-positive cells were present in aneurysmal aortae. Sequestration of VEGF-A by Ad-VEGFR-2 prevented AAA formation, with attenuation of medial elastolysis and smooth muscle depletion, mural angiogenesis and monocyte/macrophage infiltration. Treatment with anti-VEGF-A mAb prevented AAA formation without affecting further progression of established AAAs. Sunitinib therapy substantially mitigated both AAA formation and further progression of established AAAs, attenuated aneurysmal aortic MMP2 (matrix metalloproteinase) and MMP9 protein expression, inhibited inflammatory monocyte and neutrophil chemotaxis to VEGF-A, and reduced MMP2, MMP9, and VEGF-A mRNA expression in macrophages and smooth muscle cells in vitro. Additionally, sunitinib treatment reduced circulating monocytes in aneurysmal mice. CONCLUSIONS: VEGF-A and its receptors contribute to experimental AAA formation by suppressing mural angiogenesis, MMP and VEGF-A production, myeloid cell chemotaxis, and circulating monocytes. Pharmacological inhibition of receptor tyrosine kinases by sunitinib or related compounds may provide novel opportunities for clinical aneurysm suppression.
Asunto(s)
Aneurisma de la Aorta Abdominal/etiología , Elastasa Pancreática/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aneurisma de la Aorta Abdominal/metabolismo , Quimiotaxis/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Metaloproteinasa 2 de la Matriz/análisis , Metaloproteinasa 9 de la Matriz/análisis , Ratones , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sunitinib/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/análisis , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Cystic ovaries (CO) characterize a disorder frequently found in dairy cattle. However, despite the contributions by several researchers, the mechanism that leads to ovulatory failure has not yet been completely elucidated. Thus, the aim of this study was to examine the mRNA expression of bovine vascular endothelial growth factor (VEGFA)-164, VEGFA-164b and VEGF receptors (VEGFR1 and VEGFR2) by real-time PCR and protein expression by immunohistochemistry, immunofluorescence and Western blot in follicular fluid from dairy cows with spontaneous CO and in an experimental model of follicular persistence induced by prolonged treatment with progesterone. Results showed that both VEGFA isoforms and receptors were coexpressed in granulosa and theca interna cells and in follicular fluid of ovaries from all the groups evaluated. VEGFA-164, VEGFA-164b and VEGFR2 protein expression was higher in theca cells of persistent follicles from group P0 (expected time of ovulation) than in those from dominant follicles (as reference structure) from the control group (pâ¯<â¯0.05). Also, VEGFA-164 expression was higher in theca cells of cysts than in those of dominant follicles of the control group (pâ¯<â¯0.05). In follicular fluid, VEGFA-164 expression was higher in persistent follicles from group P5 (5 days of follicular persistence) than in the control, P0 and P15 groups, and higher in cysts than in dominant follicles from the control group (pâ¯<â¯0.05). This study provides evidence of an altered expression of VEGFA-164, VEGFA-164b and VEGFR2 during the formation of persistent follicles and cysts in cows. Together, these results evidence that early development of CO in cows is concurrent with an altered expression of these growth factors and that these alterations may contribute to the follicular persistence, angiogenic dysregulation and ovulatory failure found in cows with follicular cysts.
Asunto(s)
Enfermedades de los Bovinos/genética , Enfermedades de los Bovinos/fisiopatología , Quistes Ováricos/genética , Quistes Ováricos/fisiopatología , Folículo Ovárico/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Estudios de Casos y Controles , Bovinos/fisiología , Enfermedades de los Bovinos/metabolismo , Femenino , Quiste Folicular/genética , Quiste Folicular/metabolismo , Quiste Folicular/fisiopatología , Expresión Génica , Quistes Ováricos/metabolismo , Ovario/metabolismo , Ovario/patología , Ovulación/genética , Ovulación/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The discovery of Vascular Endothelial Growth Factor (VEGF), the key modulator of angiogenesis, has triggered intensive research on anti-angiogenic therapeutic modalities. Although several clinical studies have validated anti-VEGF therapeutics, with few of them approved by the U.S. Food and Drug Administration (FDA), anti-angiogenic therapy is still in its infancy. Phytochemicals are compounds that have several metabolic and health benefits. Curcumin, the yellow pigment derived from turmeric (Curcuma longa L.) rhizomes, has a wide range of pharmaceutical properties. It has also been shown to inhibit VEGF by several studies. In this review, we elaborate the effect of curcumin on VEGF and angiogenesis and its therapeutic application.
Asunto(s)
Curcumina/farmacología , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/fisiología , Antiinflamatorios , Antineoplásicos Fitogénicos , Antioxidantes , Disponibilidad Biológica , Neoplasias de la Mama/tratamiento farmacológico , Curcumina/farmacocinética , Humanos , Degeneración Macular/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Fitoterapia , Receptores de Factores de Crecimiento Endotelial Vascular/efectos de los fármacos , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Preeclampsia is a pregnancy-induced hypertensive disorder resulting from abnormal placentation, which causes factors such as sFlt-1 to be released into the maternal circulation. Though anti-hypertensive drugs and magnesium sulfate can be given in an effort to moderate symptoms, the syndrome is not well controlled. A hallmark characteristic of preeclampsia, especially early-onset preeclampsia, is angiogenic imbalance resulting from an inappropriately upregulated sFlt-1 acting as a decoy receptor binding vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), reducing their bioavailability. Administration of sFlt-1 leads to a preeclamptic phenotype, and several models of preeclampsia also have elevated levels of plasma sFlt-1, demonstrating its role in driving the progression of this disease. Treatment with either VEGF or PlGF has been effective in attenuating hypertension and proteinuria in multiple models of preeclampsia. VEGF, however, may have overdose toxicity risks that have not been observed in PlGF treatment, suggesting that PlGF is a potentially safer therapeutic option. This review discusses angiogenic balance as it relates to preeclampsia and the studies which have been performed in order to alleviate the imbalance driving the maternal syndrome.
Asunto(s)
Factor de Crecimiento Placentario/uso terapéutico , Preeclampsia/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/uso terapéutico , Animales , Femenino , Humanos , Neovascularización Fisiológica/efectos de los fármacos , Embarazo , Receptores de Factores de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
RATIONALE: Organs of the body require vascular networks to supply oxygen and nutrients and maintain physiological function. The blood vessels of different organs are structurally and functionally heterogeneous in nature. To more precisely dissect their distinct in vivo function in individual organs, without potential interference from off-site targets, it is necessary to genetically target them in an organ-specific manner. OBJECTIVE: The objective of this study was to generate a genetic system that targets vascular endothelial cells in an organ- or tissue-specific manner and to exemplify the potential application of intersectional genetics for precise, target-specific gene manipulation in vivo. METHODS AND RESULTS: We took advantage of 2 orthogonal recombination systems, Dre-rox and Cre-loxP, to create a genetic targeting system based on intersectional genetics. Using this approach, Cre activity was only detectable in cells that had expressed both Dre and Cre. Applying this new system, we generated a coronary endothelial cell-specific Cre (CoEC-Cre) and a brain endothelial cell-specific Cre (BEC-Cre). Through lineage tracing, gene knockout and overexpression experiments, we demonstrated that CoEC-Cre and BEC-Cre efficiently and specifically target blood vessels in the heart and brain, respectively. By deletion of vascular endothelial growth factor receptor 2 using BEC-Cre, we showed that vascular endothelial growth factor signaling regulates angiogenesis in the central nervous system and also controls the integrity of the blood-brain barrier. CONCLUSIONS: We provide 2 examples to illustrate the use of intersectional genetics for more precise gene targeting in vivo, namely manipulation of genes in blood vessels of the heart and brain. More broadly, this system provides a valuable strategy for tissue-specific gene manipulation that can be widely applied to other fields of biomedical research.
Asunto(s)
Vasos Sanguíneos , Encéfalo/irrigación sanguínea , Vasos Coronarios , Marcación de Gen/métodos , Animales , Barrera Hematoencefálica , Hipoxia de la Célula , Células Endoteliales , Técnicas de Inactivación de Genes , Hibridación in Situ/métodos , Ratones , Neovascularización Fisiológica , Especificidad de Órganos , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
Tumor growth and progression are critically dependent on the establishment of a vascular support system. This is often accomplished via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. VEGF ligands are overexpressed in a wide variety of solid tumors and therefore have inspired optimism that inhibition of the different axes of the VEGF pathway-alone or in combination-would represent powerful anti-angiogenic therapies for most cancer types. When considering treatments that target VEGF and its receptors, it is difficult to tease out the differential anti-angiogenic and anti-tumor effects of all combinations experimentally because tumor cells and vascular endothelial cells are engaged in a dynamic cross-talk that impacts key aspects of tumorigenesis, independent of angiogenesis. Here we develop a mathematical model that connects intracellular signaling responsible for both endothelial and tumor cell proliferation and death to population-level cancer growth and angiogenesis. We use this model to investigate the effect of bidirectional communication between endothelial cells and tumor cells on treatments targeting VEGF and its receptors both in vitro and in vivo. Our results underscore the fact that in vitro therapeutic outcomes do not always translate to the in vivo situation. For example, our model predicts that certain therapeutic combinations result in antagonism in vivo that is not observed in vitro. Mathematical modeling in this direction can shed light on the mechanisms behind experimental observations that manipulating VEGF and its receptors is successful in some cases but disappointing in others.
Asunto(s)
Modelos Biológicos , Neoplasias/terapia , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Comunicación Celular , Proliferación Celular , Técnicas de Cocultivo , Células Endoteliales/patología , Células Endoteliales/fisiología , Humanos , Conceptos Matemáticos , Neoplasias/patología , Neoplasias/fisiopatología , Neovascularización Patológica , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Transducción de Señal , Factores de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
Recently, inhibition of tumor angiogenesis has become an important anti-cancer therapy. Tumor angiogenesis is regulated by multiple signaling pathways, including VEGF and VEGF receptor (VEGF-R), FGF and FGF receptor (FGF-R), and PDGF and PDGF receptor (PDGF-R) pathways. Thus, the antiangiogenic agents, such as regorafenib, simultaneously target those receptors on vascular endothelial cells. In addition to endothelial cells, cancer cells express the three receptors, suggesting that the antiangiogenic inhibitors affect tumor cells. In fact, we previously demonstrated that regorafenib directly acted on human colorectal cancer cells and accelerated their apoptosis resistance and migration capability. Thus, we here elucidated how regorafenib induced the malignant phenotypes in colorectal cancer cells. To identify the responsible receptor among the regorafenib-targeting proangiogenic receptors, we examined the effects of a potent selective inhibitor for VEGF-R, FGF-R or PDGF-R on apoptosis resistance and migration capability. We clarified that blockade of VEGF-R, but not FGF-R and PDGF-R, induced the malignant phenotypes. We confirmed that blocking of VEGF ligands derived from colorectal cancer cells also induced the phenotypes. These results suggest that regorafenib progressed the malignancy via prevention of autocrine and paracrine VEGF signaling in colorectal cancer cells. J. Med. Invest. 64: 262-265, August, 2017.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Piridinas/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Células HCT116 , Humanos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/fisiologíaAsunto(s)
Circulación Sanguínea/fisiología , Comunicación Celular/fisiología , Membrana Celular/fisiología , Células Endoteliales/fisiología , Estrés Mecánico , Estrés Fisiológico/fisiología , Animales , Señalización del Calcio/fisiología , Humanos , Fluidez de la Membrana/fisiología , Ratones , Receptores Purinérgicos P2X4/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
Syndecans (SDC, SYND) comprise a group of four structurally related type 1 transmembrane heparan sulfate proteoglycans (HSPGs) that play important roles in tumorigenic processes. SDCs exert signaling via their protein cores and their conserved transmembrane and cytoplasmic domains or by forming complexes with growth factors (GFs). In classical Hodgkin's lymphoma (cHL), a lymphoid neoplasm of predominantly B cell origin, SDC1 and SDC4 are the active SDCs, and a number of GF (vascular endothelial growth factor, fibroblast growth factor, etc.) signaling pathways have been studied. However, despite extensive pre-clinical and clinical research on SDC-mediated GF signaling in many cancer types, there is very limited data for this interaction in cHL. Thus, this review highlights the relevant literature focusing on the potential interactions of SDCs and GFs in cHL pathogenesis. Also discussed are the pre-clinical and clinical studies targeting signaling through these pathways.
Asunto(s)
Enfermedad de Hodgkin/etiología , Transducción de Señal/fisiología , Sindecano-1/fisiología , Animales , Humanos , Lisofosfolípidos/fisiología , Neovascularización Fisiológica , Receptor IGF Tipo 1/fisiología , Receptores del Factor de Crecimiento Derivado de Plaquetas/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Esfingosina/análogos & derivados , Esfingosina/fisiología , Sindecano-1/análisis , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
Adrenocortical carcinoma (ACC) is a rare disease with an estimated incidence of only 0.7 new cases per million per year. Approximately 30-70% of the patients present with advanced disease with very poor prognosis and without effective therapeutic options. In the recent years, unprecedented progresses in cancer biology and genomics have fostered the development of numerous targeted therapies for various malignancies. Immunotherapy has also transformed the treatment landscape of malignancies such as melanoma, among others. However, these advances have not brought meaningful benefits for patients with ACC. Extensive genomic analyses of ACC have revealed numerous signal transduction pathway aberrations (e.g., insulin growth factor receptor and Wnt/ß-catenin pathways) that play a central role in pathophysiology. These molecular alterations have been explored as potential therapeutic targets for drug development. This manuscript summarizes recent discoveries in ACC biology, reviews the results of early clinical studies with targeted therapies, and provides the rationale for emerging treatment strategies such as immunotherapy.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/etiología , Carcinoma Corticosuprarrenal/etiología , Humanos , Terapia Molecular Dirigida , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Transducción de Señal , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
We identify a limited subpopulation of epidermal cancer stem cells (ECS cells), in squamous cell carcinoma, that form rapidly growing, invasive and highly vascularized tumors, as compared with non-stem cancer cells. These ECS cells grow as non-attached spheroids, and display enhanced migration and invasion. We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A-inactivating antibody reduces these responses. In addition, treatment with bevacizumab reduces tumor vascularity and growth. Surprisingly, the classical mechanism of VEGF-A action via interaction with VEGF receptors does not mediate these events, as these cells lack VEGFR1 and VEGFR2. Instead, VEGF-A acts via the neuropilin-1 (NRP-1) co-receptor. Knockdown of NRP-1 inhibits ECS cell spheroid formation, invasion and migration, and attenuates tumor formation. These studies suggest that VEGF-A acts via interaction with NRP-1 to trigger intracellular events leading to ECS cell survival and formation of aggressive, invasive and highly vascularized tumors.
Asunto(s)
Células Madre Neoplásicas/fisiología , Neuropilina-1/fisiología , Neoplasias Cutáneas/patología , Factor A de Crecimiento Endotelial Vascular/fisiología , Línea Celular Tumoral , Supervivencia Celular , Humanos , Invasividad Neoplásica , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Neoplasias Cutáneas/irrigación sanguíneaRESUMEN
Tumor cells produce vascular endothelial growth factor (VEGF) which can interact with membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth. We aimed to investigate the role of extracellular/intracellular autocrine VEGF signaling and Apatinib, a highly selective VEGFR2 inhibitor, in extrahepatic bile duct cancer (EBDC). We found conditioned medium or recombinant human VEGF treatment promoted EBDC cell proliferation through a phospholipase C-γ1-dependent pathway. This pro-proliferative effect was diminished by VEGF, VEGFR1 or VEGFR2 neutralizing antibodies, but more significantly suppressed by intracellular VEGFR inhibitor. The rhVEGF induced intracellular VEGF signaling by promoting nuclear accumulation of pVEGFR1/2 and enhancing VEGF promoter activity, mRNA and protein expression. Internal VEGFR2 inhibitor Apatinib significantly inhibited intracellular VEGF signaling, suppressed cell proliferation in vitro and delayed xenograft tumor growth in vivo, while anti-VEGF antibody Bevacizumab showed no effect. Clinically, overexpression of pVEGFR1 and pVEGFR2 was significantly correlated with poorer overall survival (P = .007 and P = .020, respectively). In conclusion, the intracellular autocrine VEGF loop plays a predominant role in VEGF-induced cell proliferation. Apatinib is an effective intracellular VEGF pathway blocker that presents a great therapeutic potential in EBDC.
Asunto(s)
Colestasis Extrahepática/tratamiento farmacológico , Piridinas/farmacología , Transducción de Señal/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Bevacizumab/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colestasis Extrahepática/patología , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Receptores de Factores de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
The role of capillaries is to serve as the interface for delivery of oxygen and removal of metabolites to/from tissues. During the past decade there has been a proliferation of studies that have advanced our understanding of angiogenesis, demonstrating that tissue capillary supply is under strict control during health but poorly controlled in disease, resulting in either excessive capillary growth (pathological angiogenesis) or losses in capillarity (rarefaction). Given that skeletal muscle comprises nearly 40% of body mass in humans, skeletal muscle capillary density has a significant impact on metabolism, endocrine function, and locomotion and is tightly regulated at many different levels. Skeletal muscle is also high adaptable and thus one of the few organ systems that can be experimentally manipulated (e.g., by exercise) to study physiological regulation of angiogenesis. This review will focus on the methodological concerns that have arisen in determining skeletal muscle capillarity and highlight the concepts that are reshaping our understanding of the angio-adaptation process. We also summarize selected new findings (physical influences, molecular changes, and ultrastructural rearrangement of capillaries) that identify areas of future research with the greatest potential to expand our understanding of how angiogenesis is normally regulated, and that may also help to better understand conditions of uncontrolled (pathological) angiogenesis.
Asunto(s)
Músculo Esquelético/irrigación sanguínea , Neovascularización Patológica/fisiopatología , Neovascularización Fisiológica/fisiología , Adaptación Fisiológica/fisiología , Animales , Capilares/fisiología , Capilares/ultraestructura , Ejercicio Físico/fisiología , Humanos , Condicionamiento Físico Animal/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
The prevalence of diabetes mellitus increased during the last century and it is estimated that 45% of the patients are not diagnosed. In South America the prevalence of diabetes and chronic kidney disease (CKD) increased, with a great disparity among the countries with respect to access to dialysis. In Ecuador it is one of the main causes of mortality, principally in the provinces located on the coast of the Pacific Ocean. The greatest single cause of beginning dialysis is diabetic nephropathy (DN). Even using the best therapeutic options for DN, the residual risk of proteinuria and of terminal CKD remains high. In this review we indicate the importance of the problem globally and in our region. We analyse relevant cellular and molecular studies that illustrate the crucial significance of glomerular events in DN development and evolution and in insulin resistance. We include basic anatomical, pathophysiological and clinical concepts, with special attention to the role of angiogenic factors such as the vascular endothelial growth factor (VEGF-A) and their relationship to the insulin receptor, endothelial isoform of nitric oxide synthase (eNOS) and angiopoietins. We also propose various pathways that have therapeutic potential in our opinion. Greater in-depth study of VEGF-A and angiopoietins, the state of glomerular VEGF resistance, the relationship of VEGF receptor 2/nephrin, VEGF/insulin receptors/nephrin and the relationship of VEGF/eNOS-NO at glomerular level could provide solutions to the pressing world problem of DN and generate new treatment alternatives.
Asunto(s)
Nefropatías Diabéticas/metabolismo , Factor A de Crecimiento Endotelial Vascular/fisiología , Angiopoyetinas/fisiología , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Salud Global , Humanos , Resistencia a la Insulina , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Proteínas de la Membrana/fisiología , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa de Tipo III/fisiología , Receptor de Insulina/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Transducción de SeñalRESUMEN
SCOPE: Cystine-knot miniproteins are bioactive molecules with a broad range of potential therapeutic applications. Recently, it was demonstrated that two tomato cystine-knot miniproteins (TCMPs) exhibit in vitro antiangiogenic activity on human umbilical vein cells. The aim of the present study was to investigate the effects of a fruit-specific cystine-knot miniprotein of tomato on in vitro endothelial cell migration and in vivo angiogenesis using a zebrafish model. METHODS AND RESULTS: The cystine-knot protein purified from tomato fruits using gel filtration LC and RP-HPLC inhibited cell migration when tested at 200 nM using the wound healing assay, and reduced nitric oxide formation probed by 4-amino-5-methylamino-27-difluorofluoscescin diacetate. RT-PCR and Western blot analyses demonstrated that vascular endothelium growth factor A dependent signaling was the target of TCMP bioactivity. Angiogenesis was inhibited in vivo in zebrafish embryos treated with 500 nM TCMP. CONCLUSION: Our results demonstrate that cystine-knot miniproteins present in mature tomato fruits are endowed with antiangiogenic activity in vitro and in vivo. These molecules may confer beneficial effects to tomato dietary intake, along with lycopene and other antioxidants. Further investigation is warranted to explore the potential of these compounds as model scaffolds for the development of new drugs.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Movimiento Celular/efectos de los fármacos , Miniproteínas Nodales de Cistina/farmacología , Células Endoteliales/efectos de los fármacos , Óxido Nítrico/biosíntesis , Proteínas de Plantas/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Solanum lycopersicum/química , Animales , Células Cultivadas , Miniproteínas Nodales de Cistina/aislamiento & purificación , Células Endoteliales/fisiología , Frutas/química , Células Endoteliales de la Vena Umbilical Humana , Humanos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pez CebraRESUMEN
Corneal neovascularization (NV), the excessive ingrowth of blood vessels from conjunctiva into the cornea, is a common sequela of disease insult that can lead to visual impairment. Clinically, topical steroid, argon laser photocoagulation, and subconjunctival injection of bevacizumab have been used to treat corneal NV. Sometimes, the therapies are ineffective, especially when the vessels are large. Large vessels are difficult to occlude and easily recanalized. Scientists and physicians are now dedicated to overcoming this problem. In this article, we briefly introduce the pathogenesis of corneal NV, and then highlight the existing animal models used in corneal NV research-the alkali-induced model and the suture-induced model. Most of all, we review the potential therapeutic targets (i.e., vascular endothelial growth factor and platelet-derived growth factor) and their corresponding inhibitors, as well as the immunosuppressants that have been discovered in recent years by corneal NV studies.